Structure-activity correlations of melanotropin peptides in model lipids by tryptophan fluorescence studies

Abstract

Steady-state and time-resolved fluorescence spectroscopy were employed in the study of the structure and interactions of alpha-MSH (alpha-melanocyte-stimulating hormone) and its analogs, [Nle4,D-Phe7]-alpha-MSH (MSH-I) and Ac-[Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10)-NH2 (MSH-II). In aqueous buffer, the fluorescence parameters of the single tryptophan of alpha-MSH and MSH-I were similar and did not allow any distinction between these molecules. On the other hand, the tryptophan fluorescence of MSH-II was notably different, reflecting its cyclic lactam turn structure. In the presence of acidic lipid vesicles, the fluorescence properties of the peptides were different, indicating structural changes on incorporation of the peptide into the liquid-crystalline phase of the lipid. No evidence of interaction was observed in the presence of the neutral lipid dimyristoylphosphatidylcholine (DMPC). The association constants for lipid-peptide interactions were compared for binding isotherms which either neglected or accounted for electrostatic effects through Gouy-Chapman potential functions. The relative order of association constants in either treatment was MSH-II > MSH-I > alpha-MSH. These results parallel the reported biological activities that show increased potencies and prolongation of response for the analogs, MSH-II and MSH-I, as compared to the native hormone, alpha-MSH. Time-resolved fluorescence results showed that the fluorescence decay of melanotropins is best described by triple-exponential kinetics. In the lipid-peptide complex, there was a change in the relative concentrations of the components, with the intermediate-lifetime component predominating compared to those in solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure and dynamics of ?-MSH using DRISM integral equation theory and stochastic dynamics

“…The compactness of the structure and the tightness of the ␤-turn in the core region are believed to be factors that increase the penetration of the peptides into the membrane. 50 It has also been suggested by Ito et al 49 that ␣-MSH may adopt its biologically active conformation only on interaction with the acidic membrane and not in the aqueous solution. However, some of the extracellular loops and some transmembrane residues of the human MC1 receptor are reported to be important for the binding of melanotropic peptides.…”

“…36,47,48 Interestingly, bicyclic analogues, in which the molecules were constrained by both a lactam cycle between positions 5 and 11 and a disulphide cycle between positions 4 and 10, were found to be far less potent than ␣-MSH in both the lizard and frog skin assays. 35 It has been suggested from recent tryptophan fluorescence studies 49 that the potency of ␣-MSH and its more potent analogues may be directly related to their ability to penetrate the acidic lipid bilayer. Nuclear magnetic resonance and electron spin resonance studies on the interaction of ␣-MSH with acidic lipid vesicles show that the interaction causes the membrane to turn more rigid 50 and, here too, increased potency of analogues was attributed to increased penetration of the peptide into the cell membrane.…”

Interaction of adrenocorticotropin peptides with microheterogeneous systems — A fluorescence study

“…Several N-terminal segments of ACTH were found to have hormonal activities and specific receptor binding properties: ACTH binds to steroidogenic receptors, while ACTH(1-10) was found to bind preferentially to central nervous receptors. The fragment ACTH (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) is an antagonist for steroidogenesis without any agonist properties [10]. ACTH may enhance memory cytotoxic responses through a combination of mechanisms such as direct cell alterations or synergy with regulatory cytokines [11].…”

Polarization effects on peptide conformations at water-membrane interface by molecular dynamics simulation

“…12 Many biologically active peptides, without stable secondary or tertiary structures in aqueous medium, could be stabilized in the presence of water᎐membrane interfaces, where their activity is expressed. 13 Several peptides have hydrophilic residues forming a domain facing the aqueous medium and hydrophobic residues located at the opposite domain facing the apolar medium.…”